The role of activated microglia in Alzheimers disease (AD) has been widely studied, but is minimally understood. Microglial cells are activated by amyloid beta peptide in vitro, and a halo of activated microglial cells surrounds senile plaques in AD brain, leading some investigators to speculate that microglial cells are in part responsible for neurodegeneration in and around plaques. However, evidence for this hypothesis is circumstantial, and microglial cells also secrete neurotrophins, indicating that activated microglial cells in the vacinity of amyloid deposits could serve to support neuronal survival under local conditions of stress. This proposal seeks to determine the role of activated microglal cells in models of AD-like pathology in vitro and in AD brain, and specifically tests the hypothesis that microglial activation can be neuroprotective both in vitro and in vivo. Specific aim 1 tests the hypothesis that microglial activation is neuroprotective in vitro by modulating miroroglial cell activation and determining resultant neurnal pathology and glial response following amyloid beta peptide toxicity, excitotoxicity, or hypoglycemia in organotypic hippocampal cultures. Specific aim 2 tests the role of the neuroprotective cytokine tumor necrosis factor (TNF) in microglial- mediated neuroprotection by applying the paradigms listed in specific aim 1 to cultures drawn from TNF receptor deficient mice. Specific emphasis will be placed on the role of TNF-induced MnSOD and iNOS activation, and the selective induction of apoptosis over necrosis. Specific aim 3 will probe AD and control brain tissue for TNF and the TNF signalling moieties listed in specific aim 2 to determine if these pathways are activated in either neurons or glial cells of AD brain. Particular emphasis will be placed on identification of pathways activated in neurons and glial cells surrounding diffuse, non-neuritic amyloid deposits versus those activated in cells in the vacinity of dense core senile plaques. Collectively, the above studies will help elucidate the role of neuron/glial interactions in AD pathology, and potentially highlight novel therapeutic strategies for AD research, as well as for other neurodegenerative disorders of aging such as Huntington's disease and stroke.